Common to all vocal communication systems is matching between hearing and utterance. The match can be achieved via learning (as in song birds or humans) or be innate or largely unlearned (as in frogs or non-human primates), but in both cases strong selective pressures have shaped the ability to produce appropriate vocal responses to specific acoustic signals. How this task is accomplished by the neural networks that produce vocal responses is not well understood in part because of the complexity of most experimental systems. The long-term goal of this research is to understand neural mechanisms for auditory/vocal communication through exploration of a well-established model system: vocal communication in the South African clawed frog, Xenopus laevis. Many aspects of the neural circuitry underlying vocal production have been worked out and a reduced preparation - the isolated brain- can be induced to produce fictive calling. We are particularly interested in understanding the role of a forebrain nucleus, the ventral striatum (VST) which - uniquely in the Xenopus vocal circuit - receives auditory information and projects directly to the major hindbrain afferent of vocal motor neurons, nucleus DTAM. The central hypothesis of this research program is that the VST participates in selecting an appropriate vocal pattern in response to specific acoustic input. To investigate this hypothesis we first need additional information about how the VST functions as a pre-motor and an auditory nucleus. Production of vocal signals is controlled by a set of neuromodulators whose effects depend on endocrine state. Thus an additional goal of this phase of the research is to understand how neuroendocrine factors such as gonadotropin and neuromodulators such as serotonin affect the function of the VST in the vocal circuit. Our experimental approaches combine in vitro and in vivo methods. We use the isolated brain preparation we have recently developed to understand the participation of various components of the auditory/vocal neural circuit in the vocal response;cellular and molecular approaches are combined with stimulation and electrophysiological recording. We will test proposed mechanisms in vivo to determine to what extent whether they actually participate in the endogenous control of vocal behavior in the animal. The ability of forebrain to influence vocal output could derive from an ancient set of neural connections that have been elaborated in some vertebrates. If so, the forebrain/hindbrain, auditory/vocal system in Xenopus laevis should provide very interesting insights into the ways in which neural networks for communication can function as well as suggesting ways in which communication disorders can be treated. PUBLIC HEALTH RELEVANCE Several human speech disorders are attributable to impaired function of auditory/vocal linkages. Deafening before language acquisition has profound effects on development and communicative skills [64]. When prelingually deaf adults receive cochlear implants, the quality of the speech production improves along with speech perception [65]. Articulation disorders, which are commonly regarded as motor in origin, such a stuttering and aphasia, can improve, sometimes quite dramatically, by auditory cues delivered in a social context such as choral speaking [66] and singing [67]. The effects of choral speaking, in particular, have been proposed to be mediated by the "mirror neuron" system that supports imitation in general and vocal imitation in particular. form the basis for "mirror neuron" systems proposed to function in human speech and learned bird song. Auditory/vocal linkages in forebrain may, in fact, arise from a set of evolutionarily ancient mechanisms that link hearing to utterance. If so, understanding auditory/vocal matching in Xenopus could provide a set of candidate neural mechanisms whose prevalence and utility can then be investigated more widely.